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1 Testosterone replacement therapy - testosterone undecanoate (Andriol) Geurts TBP, Coelingh Bennink HJT Journal für Urologie und Urogynäkologie 2000; 7 (Sonderheft 1) (Ausgabe für Schweiz) Homepage: Online-Datenbank mit Autoren- und Stichwortsuche Indexed in Scopus Member of the P. b. b. 0 2 Z M, V e r l a g s p o s t a m t : P u r k e r s d o r f, E r s c h e i n u n g s o r t : G a b l i t z

2 T. B. P. Geurts, H. J. T. Coelingh Bennink THERAPY (ANDRIOL ) PARTIAL ANDROGEN DEFICIENCY IN AGEING MALE (PADAM) The phenomenon During the normal ageing process in men there is a gradual decline in testicular function, including a fall in serum levels of total testosterone and of bioavailable testosterone, testosterone not bound by SHBG (Fig. 1) [1, 2]. There is great interindividual variability in the age-related changes in testicular function, and only some men become hypogonadal, as defined by serum total testosterone levels below the normal range for young adult men [3]. That such a decline in testosterone levels takes place has only been generally accepted very recently and few studies of hormone replacement for older males have been published (Table 1). Reports in the 1960s and 1970s of decreased plasma concentrations in elderly men were followed by a number of publications that did not confirm this. The inconsistencies of these results were attributed to differences in the characteristics of the men studied (eg, health and socio-economic status, smoking, alcohol consumption) and to differences in study design (eg, the time of day at which blood samples were taken). A number of more recent, well-designed studies, however, have shown convincingly that androgen levels do decrease with age [1, 4, 5]. The Massachusetts Male Ageing Study [1] included 415 healthy men and 1294 men with one or more ailments, aged between 39 and 70 years. In both groups of men, free testosterone levels were found to decline by 1.2 % per year, albumin-bound testosterone, by 1.0 % per year and SHBG, the carrier protein that binds 60 % of circulating testosterone, increased by 1.2 % per year. The net effect of these changes was that total serum testosterone levels decreased more slowly (0.4 % per year) than the free or albumin-bound testosterone pools alone. Testosterone levels were % lower in the less healthy group of men, which included men with obesity compared with the healthy group but the trends in the two groups did not differ significantly. It has also been found that the circadian rhythm (early morning rise) in serum testosterone levels found in normal young men is markedly attenuated or absent in healthy elderly men [6]. This change makes it even more important to control the time of day at which samples are taken for testosterone measurements. For some of its biological actions testosterone has to be converted to DHT most of which is produced in a local conversion of testosterone in target organs. Only 20 % of DHT is secreted by the testis; the plasma DHT originates in the main from leakage of DHT from target organs into the general circulation [4]. There have been conflicting reports of the relationship of serum DHT levels with ageing: including reports of decreased levels, unchanged levels and increased levels. In the Massachusetts Male Ageing Study DHT did not show a significant age-related trend. However, the reduction products of DHT, androstanediol and its glucuronide, which are considered to be biochemical indices of androgen action in target organs, were found to decrease with age [1, 4]. There is no established definition of testosterone deficiency in older men. Tremblay and Morales [7] have suggested that patients should be treated for specific indications on the basis of both clinical symptoms and serum testosterone levels. This suggestion is consistent with the views of Tenover [8] who notes that it is probable that the level of testosterone that can be described as a deficiency varies between individuals and between target organs. Tenover [8] has also pointed out that depending on the definition of hypogonadism, the proportions of men affected differ greatly. If hypogonadism is defined as having a serum testosterone level in the lowest quintile and gonadotropin levels in the highest quintile, about 4 % of men in the age range are hypogonadal but if the definition were to embrace men of 55 and over whose serum testosterone levels are below the lower normal range Plasma testosterone (nmol/l) Figure 1: Changes in plasma testosterone levels with age, based on the data of Vermeulen [2] Age (years) 24 J. UROL. UROGYNÄKOL. 1/2000 Special Edition

3 for young adults, this would include about 20 %. Further, if the definition were based on unbound or bioavailable testosterone the prevalence might rise to about 50 %. Reasons for the decline in testosterone Most testosterone is produced by the Leydig cells of the testis (95 %) and its secretion is regulated by the pituitary through the release of LH which is in turn under the control of the hypothalamic luteinizing hormone releasing hormone. There is no clear consensus about the endocrine mechanism of the gradual decline in testosterone levels with age. It seems likely that the lower testosterone levels are the result of changes at many levels of the hypothalamic-pituitary-gonadal axis [9, 10]. That a primary testicular cause is one factor in the decreased androgen levels in elderly men is suggested by the decrease in the number of Leydig cells and the impaired testicular perfusion. The testicular response to gonadotropins is diminished in older men; gonadotropic response to androgen suppression is attenuated and the pulsatility of the gonadotropin-releasing hormone (FSH- and LH-releasing hormone) pulse generator is altered. Co-existing diseases, malnutrition and concomitant medications can also affect serum testosterone levels; in the Massachusetts Male Ageing Study the testosterone levels of the less healthy males were lower [1]. Gooren [4] raised the possibility that ageing might lessen the effects of androgens through a loss of sensitivity to testosterone in target tissues perhaps as a result of changes in receptor number or affinity, or in postreceptor mechanisms. This possibility has not been investigated but it might limit the benefits of androgen supplementation in older men. Free and bioavailable testosterone Both free and bioavailable (free and albumin-bound) testosterone levels decline more rapidly with age than do total testosterone levels [2, 11 13]. In the Massachusetts Male Ageing Study plasma free testosterone levels declined by 1.2 % per year, and albumin-bound testosterone declined by 1.0 % per year while total testosterone decreased by only 0.4 % per year [1]. The more pronounced decrease in free than in total testosterone is explained by the age-dependent increase in the binding capacity of SHBG (1.2 % per year). The decline in bioavailable testosterone occurs earlier than the decline in total testosterone [12, 13]. Bioavailable testosterone levels have been found to correlate with a number of age-related cognitive and physical measures [14] and appears to be a more sensitive marker of PADAM than free testosterone. EFFECTS OF THE DECLINE IN Ageing in men is sometimes associated with a cluster of clinical problems including: osteoporosis muscle weakness and wasting (strength and energy) changes in body composition decreased body hair decreased hematopoiesis sexual dysfunction memory loss decreased general well-being Some or all of these problems may be related to the decline in testosterone levels or to reduced androgen sensitivity in older men [8, 9]. Other symptoms that have been suggested as possibly due to testosterone deficiency include sweating, hot flushes, insomnia, nervousness, irritability and lethargy, lack of motivation, low mental energy, depressive symptoms, low self-esteem, decreased vigour and physical energy [7]. Osteoporosis The problem of osteoporosis and hip fractures in elderly men is increasing with the growing numbers of elderly people since the incidence of hip fractures increases with age. In men over 65 years of age, the incidence of hip fractures is about 4 or 5 per thousand [12]. The mortality rate within 6 months after hip fracture in elderly men is 20 % and only 41 % of the survivors recover to their former level of functioning [15, 16]. Several lines of evidence indicate that testosterone levels are a factor in the development of osteoporosis in ageing men. Hypogonadism in elderly white males is associated with an increased risk of minimal trauma hip fracture: in one study involving 17 men with minimal trauma hip fractures and 61 controls, 59% of those with hip fractures but only 18 % of the controls J. UROL. UROGYNÄKOL. 1/2000 Special Edition 25

4 Table 1: Studies of the use of testosterone supplementation therapy for the treatment of PADAM Reference Study design Type/no. of patients Daily Testosterone Results Safety/other aspects dose/duration Romanelli et al [34] Uncontrolled 6 men, low androgen 80 mg TU/day Improved libido and Some of the effects levels and PADAM for 8 months sexual activity, may be placebo symptoms, age 53 to improved well-being effects 62 years and disappearance of symptoms Isidori et al [33] Double blind 20 men with PADAM 10 men given Significant increase placebo-controlled symptoms, age 45 to 80 mg TU/day in libido, erections 75 years for 8 weeks Janowsky et al [39] Double blind Healthy older men Scrotal patches Significant enhancement Oestradiol was aged years containing 15 mg of spatial cognition, but inversely correlated T for 3 months no changes in memory, with spatial cognition motor speed, cognitive flexibility or mood Morley et al [20] Open, alternately 14 men aged men given Significantly increased Decreased total assigned cases years with bioavailable 200 mg TE/2 weeks right-hand muscle cholesterol but no (treated) and T < 70 ng/dl (some for 3 months, 6 strength and osteocalcin change in HDL controls (untreated) impotent) controls concentration (suggesting cholesterol. improved osteoblastic Decreased BUN: creafunction), increased tinine ratio. PSA haematocrit tended to increase Sih et al [25] Randomized 32 men hypogonadal 17 given 200 mg Bilateral grip strength No significant changes placebo-controlled (bioavailable T TC every 2 weeks and haemoglobin levels in PSA or prostate < 60 ng/dl). for 12 months were significantly on DRE. 3 on Age 58 to 74 years increased. Leptin placebo and 7 on levels decreased TC withdrew. 3 on significantly more in TC withdrew because TC group. No of abnormal significant change haematocrits in memory Tenover [3] Double-bllind 13 healthy men aged 100 mg TE/week im. Lean body mass Reduced total and LDL randomized years with serum for 3 months significantly increased cholesterol. No enlargeplacebo-controlled T 13.9 nmol/l and hydroxyproline ment or abnormality of crossover excretion decreased prostate but a sustained suggesting reduced increase in PSA bone resorption. Increased haematocrit Tenover 1998 Double-blind 70 healthy men aged 3 groups given Preliminary results. Both No increase in serum PSA unpublished randomized 65 to 83 years with 150 mg TE/2 weeks or T groups showed increased and no change in the morning T < 13 nmol/l 150 mg TE + finasteride bone density, increased risk of prostate problems. or placebo for 3 years muscle mass and reduced Total and LDL cholesterol body fat cf placebo group. reduced. So far not Further analysis of data fully analysed, and will give results for unpublished libido and cognition Urban et al [24] Uncontrolled 6 healthy men aged TE injections weekly Increased muscle strength years with for 4 weeks. Doses in hamstring and quadriceps, serum T < 480 ng/dl adjusted to keep serum increased fractional synthetic or less T in the range rate of muscle protein. mrna ng/dl concentrations suggesting stimulation of IGF-1 T = testosterone; TC = testosterone cypionate; TE = testosterone enanthate were hypogonadal [17]. Tenover [8] briefly reviewed several shortterm studies (6 weeks to 18 months) which suggest that testosterone supplementation, in the short-term at least, may have benefits for BMD and bone turnover. There is an increased 26 J. UROL. UROGYNÄKOL. 1/2000 Special Edition incidence of osteoporosis and related fractures in men after orchidectomy for prostatic cancer [18]. Further, castration or treatment of older men with gonadotropin-releasing hormone analogues can lead to rapid declines in BMD [8]. A few studies have been reported to show a correlation between testosterone levels and BMD while others have failed to demonstrate an age-independent association between testosterone and BMD in men [12].

5 There are a number of possible mechanisms by which testosterone may affect bones. It may affect them directly via androgen receptors or via cytokines or growth factors. Alternatively the effects of testosterone may be indirect via aromatisation to oestrogens, via an increase in muscle mass and strength (mechanical loading), via calciotropic hormones or via renal handling of calcium, phosphorus and vitamin D. Increases in bone mineral density were seen in hypogonadal men treated with testosterone supplements for up to 16 years [19]. Most (52) of the 72 patients included in the study were treated with intramuscular testosterone enanthate: the remainder received other formulations including oral TU in three cases. Serum testosterone levels increased to the normal range in all of the treated men. The most significant rise in bone mineral density (trabecular, lumbar spine) was during the first year when it rose by about 26 %. Long-term therapy maintained bone mineral density in the reference range in all cases [19]. The results of the study of the effects of long-term testosterone therapy on bone density in 14 hypogonadal men with Klinefelter s syndrome, mentioned earlier, were much less encourageing [20]. The bone mineral densities of the treated patients were significantly lower than those of normal age-matched controls and there was no correlation between the duration of treatment and bone mineral density. There is some evidence from studies in older men that testosterone substitution improves BMD. In an open study in which eight men aged years with bioavailable testosterone levels below 70 ng/ml were given 200 mg TE every 2 weeks for 3 months, osteocalcin concentrations were significantly increased, suggesting improved osteoblastic function [21]. In a double-blind randomised crossover study of 13 men aged 57 76, treated with 100 mg TE every week for 3 months, hydroxyproline excretion decreased, suggesting reduced bone resorption [3]. Preliminary results from a long-term randomised placebo-controlled trial have shown steady increases in BMD in men treated with testosterone enanthate injections (Tenover, 1998, unpublished). In this latter study, 70 healthy men, aged years, with morning total testosterone levels below 13 nmol/l were randomly assigned to receive for 3 years: (1) 150 mg testosterone enanthate intramuscularly every 2 weeks and finasteride (a 5a-reductase inhibitor that prevents the production of DHT) or (2) testosterone plus a placebo pill or (3) placebo injections and pills. After 3 years of treatment, men receiving testosterone with or without finasteride showed an 8 % increase in BMD in the lumbar spine and a 3 % increase at the hip. Muscles and body composition Normal ageing in men results in a decrease in muscle mass, a decline in muscle strength and increases in upper and central body fat [8]. Hypogonadal men show similarly reduced lean body mass, decreased muscle strength and increased adipose tissue compared with men with normal testosterone levels. These changes in body composition have been ascribed to lower testosterone levels in both hypogonadal and elderly men. There is no conclusive evidence that testosterone is at the root of these changes in body composition, but young hypogonadal men treated with testosterone replacement have been reported to show increases in lean body mass, muscle size and strength [22]. Further, testosterone has been shown to be associated with muscle mass in animals [23]. It has also been suggested that the ability of testosterone to protect against muscle mass loss may be mediated through insulin growth factor 1(IGF-1), the serum levels of which have been found to fall significantly with age [12, 24]. Several interventional studies suggest that testosterone replacement therapy in older males may enhance muscle strength, increase lean body mass and decrease fat mass (Table 1) [12]. In one open study healthy elderly men treated with testosterone enanthate for 4 weeks showed increased muscle strength in the hamstring and quadriceps muscles, increased fractional synthetic rate of muscle protein and increased IGF-1 mrna concentrations [24]. Sih et al [25] assessed the effects of testosterone cypionate treatment for 12 months in a placebo-controlled randomized trial in hypogonadal men aged 50 years or above. The testosterone treatment significantly improved grip strength. Sih et al. used grip strength as an indicator of muscle strength and saw encourageing improvement but the effects on lower extremity strength, also an important factor in this age group, were not assessed. There was also a significant increase in right- J. UROL. UROGYNÄKOL. 1/2000 Special Edition 27

6 28 J. UROL. UROGYNÄKOL. 1/2000 Special Edition Table 2: Published reports of the use of oral testosterone undecanoate (TU) to treat hypogonadism Reference Study design Type/no. of Daily TU dose/ Results Safety/other aspects patients treated duration with TU Bancroft and Wu [48] Placebo- 8 hypogonadal 160 or 240 mg/day Erections to films were not controlled affected by treatment but crossover erections to fantasies were significantly improved. Conway et al [49] Comparative 14 hypogonadal 240 mg for 4 weeks 3/14 patients reported 6/14 had gastrointestinal prospective adequate effects (libido, symptoms but continued randomized potency, muscular strength and treatment. crossover general well being). Franchi et al [50] Open baseline 42 hypogonadal 80 mg/day for 16 All patients noticed a comparison weeks remarkable increase in sexual, physical and mental activity. Franchi et al [40] Comparison 34 hypogonadal mg/day Increase in libido and sexual No changes in size and with previous for 8 months physical, and/or mental consistency of prostate. treatment activities. Preferred over No abnormal lab values. TU injectable regimes. No gynecomastia. Franchimont et al [41] Baseline 10 hypogonadal mg/day Increased libido and sexual comparison for 9 weeks activity in 9 patients, increased mental activity in 7, physical activity in 2. Gooren [29] Comparison with 8 hypogonadal mg/day No difference in sex functions One man did not complete, previous treatment and mood compared with choosing to return to parenteral previous testosterone treatment. treatment because of reduced sexual appetite and energy. Jockenhövel et al [36] Comparison with 13 hypogonadal men 160 mg/day for 30 Increased haemoglobin other androgen weeks and haematocrit replacements Luisi and Franchi [30] Double-blind 12 hypogonadal men 120 mg TU/day for Significant improvements randomised (TU) 4 weeks cf 150 mg in libido, erections, ejaculations comparison mesterolone and mood compared with mesterolone Maisey et al [42] Comparison with 76 hypogonadal mg/day for Improvements in sexual function, 8(/10) patients dropped out previous treatment men (10 dropped out) 9 weeks (doses modi- frequency of intercourse, work because of side-effects, mainly in 71 patients fied as needed) efficiency, ability to concentrate Gl. Sig. rise in plasma testosterone and changes in sporting activities. correlating with plasma TU. Morales et al [51] Comparison 23 impotent 120 mg/day for Measurable improvement in None of conventional with baseline hypogonadal men 60 days+ sexual interest in 15. Complete biochem. measures response in 10. correlated with outcome. O Carroll et al [45] Dose-ranging, 8 hypogonadal men 40, 80, 120 and Dose-response relationship found double-blind 160 mg/day in 4 for frequency of sexual thoughts, successive 1-month arousal accompanying sexual treatments thoughts and well-being. Sleep erections improved significantly. Papadimas et al [43] Comparative 9 hypogonadal 120 mg/day for 4 All 9 reported improved libido and (mesterolone) weeks sexual activity. Mental activity randomized improved in 8 patients and physical double-blind activity improved in 7. Skakkebaek et al [31] Double-blind 12 hypogonadal 160 mg/day for 8 TU had a significant effect on all Rise in plasma testosterone crossover (6 hyper- and 6 weeks measures of sexual interest and did not reach normal range in comparison with hypogonadotrophic) behaviour. Responses were similar some cases. DHT rose more. placebo in the two groups.

7 Wong et al [20] Comparison of 14 Klinefelter s 240 mg/day cf No correlation between duration long-term oral syndrome 250 mg TE/3 weeks of treatment and bone mineral TU with im TE for 2 12 years density. These methods of T replacement don t reverse decline in bone mass in Klinefelter s Wu et al [52] Randomized 4 Klinefelter s 160 mg/day for 8 Inconclusive results re sexual interest. Increase in circulating double-blind syndrome, low weeks No effect on mood, energy or DHT more marked than crossover normal testosterone erectile responsiveness in the lab. increase in testosterone comparison of and normal sexual TU and placebo activity hand muscle strength in the open study of Morley et al (Table 1) [21]. In the studies of Tenover [3, unpublished 1998] (Table 1), a significant increase in lean body mass was seen in the 3-month study with testosterone enanthate and in the 3-year study there was a 4-kg increase in muscle mass compared with a 3-kg drop in muscle mass in the placebo group. In the long-term controlled study of Tenover (1998) there was also a 16 % reduction in body fat. Testosterone had no significant effect on body composition in the study by Sih et al [25]. The dosedependency of the anabolic effects of testosterone is, however, unknown so dose could be a contributory factor. Another reason for the discrepancy might be differences in the methods used to measure body composition. Sexual dysfunction Several studies have shown that there is an age-related decrease in sexual interest and activity, particularly an increased prevalence of erectile dysfunction [4]. In the Massachusetts Male Ageing Study the combined prevalence of impotence (minimal to complete) was 52 % in men aged years [26]. The prevalence of complete impotence tripled from 5 % to 15 %, and that of moderate impotence doubled from 17 to 34 % between the ages of 40 and 70 years. Age was the most predictive variable for impotence. However, heart disease, hypertension, diabetes mellitus, associated medications and psychological troubles all increased the probability of impotence [26]. Of the 17 hormones measured, however, only the androgen metabolite, dehydroepiandrosterone sulphate, showed a strong correlation with impotence. DHT and cortisol showed small effects on minimal impotence only. There was no correlation with impotence for total testosterone, SHBG or any of the androgen metabolites, estrogens, prolactin or the pituitary gonadotropins. Unfortunately, bioavailable testosterone was not measured in this latter study. The classification of men into four impotence categories (no, minimal, moderate or complete impotence) was based on the answers to a questionnaire about sexual activity and erections. A cross-sectional study of 220 men aged 41 to 93 years showed that total and free plasma testosterone levels declined and gonadotropins increased in parallel with a decline in sexual activity with orgasm, morning erections, sexual thoughts and sexual enjoyment [27]. Decreases in free testosterone and increases in LH correlated significantly with the decline in the measures of sexual functioning (except sexual enjoyment in the case of free testosterone). Hormonal changes seemed to be more closely related to sexual activity and morning erections than to libido. The hormonal factors did not account fully for the age-related decline in sexual functioning. Similarly, in a study of 77 healthy men aged years bioavailable testosterone and the ratio of bioavailable testosterone to luteinizing hormone were correlated with several sexual behavioural dimensions: frequency of sexual thoughts and desire, ease of arousal, frequency of sleep erections and strength of coital erections [28]. Total testosterone, J. UROL. UROGYNÄKOL. 1/2000 Special Edition 29

8 estradiol and prolactin showed few or no such relationships. Androgen-replacement studies in hypogonadal men indicate that androgens are more important in sustaining sexual desire and sleep-related erections than in maintaining erectile response to external stimuli [4]. In men under 50 years old testosterone levels of about 60 % of the reference values are sufficient to maintain sexual function [4, 29]. Whether this applies to ageing men is not clear. Studies in hypogonadal men indicate that TU therapy has significant effects on libido, sexual activity and sexual responses such as enjoyment, erections and ejaculation (Table 2) [30, 31]. As noted above, Carani et al [32] treated impotent men (aged years) with mild hypogonadism with oral TU (160 mg/day) and found that TU improved sexual function in men with low free testosterone levels but not in those with normal levels although total testosterone levels were similar. The limited studies carried out so far in older men showing symptoms of PADAM indicate that testosterone replacement with oral TU may have beneficial effects on libido, erections and frequency of intercourse (Table 1) [33, 34]. It seems clear that the prevalence of erectile dysfunction increases with age but the overall picture of the relationship between declining testosterone levels and increasing sexual dysfunction is not yet certain. From the results of the Massachusetts Male Ageing Study there does not appear to be a simple or direct relationship between impotence and androgen levels in ageing men. Other studies indicate that some aspects of sexual functioning are correlated with plasma testosterone levels. The extent to which testosterone replacement in elderly men can improve sexual functioning remains to be clarified. Decreased hematopoiesis Androgens are known to stimulate erythropoiesis; they increase reticulocyte counts, hemoglobin levels and bone marrow erythropoietic activity in mammals and castration has the opposite effects. Testosterone stimulates the renal production of erythropoietin and may have a direct effect on erythropoietic stem cells [35]. Young hypogonadal men have lower red blood cell counts and hemoglobin levels than their age-matched controls. Healthy older men tend to have similar or slightly lower hematocrits than normal young adult men [35]. Jockenhövel et al [36] investigated the effects of different forms of androgen substitution on hemoglobin concentrations and hematocrits in 55 hypogonadal men (Table 2). Both hemoglobin levels and hematocrits were significantly increased with oral TU, with T implants and TE injections, whereas no increase was observed in the mesterolone group. Thus for stimulation of erythropoiesis, testosterone levels within the low normal range (as seen with TU) were sufficient. This suggests a possible advantage, from the safety viewpoint, of using TU to treat older men. The authors conclude that it is testosterone and not DHT that stimulates erythropoiesis in a dosedependent manner. The authors also suggest that blood counts should be monitored during highdose testosterone substitution since some individuals respond with an exaggerated increase in hemoglobin and hematocrit. The need for such monitoring is emphasized by the fact that in one study, using testosterone cypionate in older men, 3/17 patients dropped out because of abnormally high hematocrits [25]. Memory loss and impaired cognitive function There is some evidence that testosterone enhances memory both in mice and in humans although it is not yet clear whether decreasing testosterone levels have a role in modulating age-related cognitive decline [12]. A study in mice has suggested that impaired cognitive functioning in older mice of a particular strain was due to an interaction of ageing and reduced testosterone levels [37]. Testosterone supplementation alleviated impaired learning and memory of a foot shock avoidance task in these mice. A significant decline in spatial cognition with ageing has also been reported [38]. One study in older men showed an improvement in spatial cognition after 3 months of treatment with testosterone scrotal patches but there were no changes in verbal and visual memory, motor speed, cognitive flexibility or mood (Table 1) [39]. Testosterone supplementation reduced the endogenous production of estradiol and serum estradiol concentrations were inversely related to 30 J. UROL. UROGYNÄKOL. 1/2000 Special Edition

9 spatial cognitive performance. Further evidence that testosterone replacement in older men does not affect memory comes from the study of Sih et al [25]. In this 1-year placebo-controlled study of testosterone replacement therapy (using intramuscular testosterone cypionate) in older hypogonadal men there was no effect on memory. Studies in younger hypogonadal men have suggested that testosterone replacement improves concentration ability or mental activity [40 43]. Decreased general well-being Hypogonadal young men and some older men given testosterone supplementation have variously reported improved mood, improved sense of wellbeing, decline in anxiety, and improved feelings of energy [3, 44 46]. Treatment with TU of 80 mg/day in elderly men with low plasma testosterone improved general well-being after three months of treatment [34]. PATIENT SELECTION Two groups have recently presented their approaches to different aspects of the decision about which patients should be treated for PADAM. Morley [20] has proposed a questionnaire to evaluate the symptoms of androgen deficiency and Tremblay and Morales [7] have published recommendations based on serum concentrations of bioavailable testosterone. A combination of these two approaches seems likely to be helpful. The questionnaire suggested by Morley et al consists of the following ten questions: 1. Do you have a decrease in libido (sex drive)? 2. Do you have a lack of energy? 3. Do you have a decrease in strength and/or endurance? 4. Have you lost height? 5. Have you noticed a decreased enjoyment of life? 6. Are you sad and/or grumpy? 7. Are your erections less strong? 8. Have you noted a recent deterioration in your ability to play sports? 9. Are you falling asleep after dinner? 10. Has there been a recent deterioration in your working performance? The validity of this questionnaire as a means of identifying older men with reduced testosterone levels was assessed in 316 men aged years. Low bioavailable testosterone levels (< 70 ng/ dl) were present in 25 % of these men; the questionnaire identified this group with a sensitivity of 88 % and a specificity of 60 %. In 21 patients treated with testosterone (no details given), scores in the questionnaire improved in 18 patients. The results suggest that the questionnaire may have potential in the assessment which patients should be treated for PADAM. The recommendations of Tremblay and Morales [7] for the treatment of PADAM include the following guidelines for patients who should be treated: Treatment with supplemental testosterone therapy should be given for specific indications to patients with clinical symptoms and physical manifestations of hypogonadism. Laboratory assessment is essential: the diagnosis of hypogonadism should ideally be based on finding levels of serum bioavailable testosterone below the lower limits of normal (2 2.5 nmol/l in Canada) in morning blood samples on two or more occasions. If serum bioavailable testosterone cannot be measured, free testosterone underestimates bioavailable testosterone and may therefore be misleading. Patients with suspected secondary hypogonadism (of hypothalamic-pituitary origin) should not be given testosterone until endocrine investigations are complete. Before starting testosterone therapy patients should have hematocrit, serum lipid profile and prostate specific antigen determinations and should be given a digital rectal examination. Mild benign prostatic hypertrophy is not an absolute contraindication to therapy: patients with few urinary tract obstructive symptoms may be suitable for therapy but those with advanced obstructive symptoms are not. Breast cancer, prostate cancer and sleep apnoea are all contraindications to therapy. In the case of breast cancer this is because testosterone treatment may increase oestrogen levels. Patients suspected of having prostate cancer, after digital rectal examination and/or serum prostate-specific antigen measurements, should be fully investigated. The recommendations of Tremblay and Morales [7] also include J. UROL. UROGYNÄKOL. 1/2000 Special Edition 31

10 guidelines for the assessment of patients who are being treated: In the early phase of treatment patients should be assessed every 3 months. At these times, the response to therapy should be assessed, a digital rectal examination should be done and, if the patient is over 40 years old PSA should be determined. If the PSA level is above 4 ng/ ml the patients should be examined by a urologist. Patients who remain stable may subsequently be assessed every 6 months when their lipid profiles, hemoglobin levels and hematrocrits may also be considered. Clinical response is a better guide to the dose required than are serum levels of bioavailable testosterone which may fluctuate considerably (depending on the treatment) (In the case of oral TU, doses should be adjusted on an individual basis). TREATMENT IN PADAM So far there have been few studies of the use of oral TU to treat PADAM: small groups of older men were studied; the studies were of less than 12 months duration and the outcomes reported were limited and varied. However, taken together with the results of studies of the use of oral TU in other indications, such as hypogonadal states in men of all ages, these limited studies add weight to the view that the potential of oral TU as an option in the treatment of PADAM should be explored. An uncontrolled study was carried out in six men, aged between 53 and 62 years [34]. The men presented with decreased libido and potency, insomnia, palpitations, poor efficiency at work, impaired concentration and memory, irritability, mild depression, apathy and low circulating androgen levels, and without apparent prostatic pathology. The men were given 80 mg TU orally/day for 8 months. Five of the six patients had not had intercourse for some time and the other made infrequent generally unsuccessful attempts at intercourse. Plasma testosterone levels rose steadily during the treatment period from a mean of to ng/dl after 7 months. Plasma levels of DHT and estradiol also rose steadily while FSH and LH declined during the treatment period. By the third month of treatment all patients reported an improved general feeling of wellbeing and disappearance of complaints. Libido also increased and four of the six reported having intercourse. Further improvements occurred subsequently and all of the patients and their partners were very satisfied with the treatment. In a double-blind placebocontrolled study oral TU also showed promising results in men affected by PADAM [33]. Half of the group of 20 men, aged 45 to 75 years were given 80 mg TU/ day for 8 weeks while the other ten received placebo. There were significant increases in plasma testosterone concentrations in the treated group, compared with the control group both 4 and 8 weeks after the start of treatment. After 8 weeks the men in the treated group showed significant increases in both libido and erection scores compared with the placebo group. There was also an increase in the score of ejaculation but this was not statistically significant. The potential risks of testosterone treatment of older men are elevation of red blood cell count, exacerbation of sleep apnoea, fluid retention, exacerbation of benign or malignant prostate disease and increased risk of cardiovascular disease. Bhasin and Tenover [47] expressed concern at the high dropout rate in the study of Sih et al [25] using testosterone cypionate. Three men dropped out because of increases in hemoglobin reflecting the fact that older men seem to show more marked increases in hemoglobin than do younger men in response to testosterone injections. Clearly there is a need to monitor hemoglobin and hematocrit levels as was also suggested by Tremblay and Morales [7]. Concerns about prostate enlargement, prostate cancer and coronary heart disease risk are clearly greatest for older men. Existing safety reports are mainly for younger men (and the numbers involved are relatively small) but in the case of TU they are encourageing. The use of testosterone supplementation in older men will need careful ongoing monitoring of all aspects of safety. In conclusion, oral TU does not appear to induce prostate enlargement beyond that seen in 32 J. UROL. UROGYNÄKOL. 1/2000 Special Edition

11 eugonadal men of the same age. As with other testosterone formulations, however, prostate cancer is an absolute contraindication to the use of TU. The effects of oral TU on lipid and lipoprotein profiles are not yet clear but the evidence so far suggests that TU often has generally favourable effects, particularly by reducing total cholesterol. Finally, oral TU does not appear to have any detrimental effects on liver function. CONCLUSIONS TU has the advantage over other preparations that it is easy to administer since it can be taken orally. Dose flexibility and the possibility to immediate interruption of treatment are easy for patients themselves. As a result of its lymphatic absorption, TU administration results in variable serum testosterone levels within the lower normal range, depending on the daily dose administered. There is evidence that testosterone therapy may have benefits for some older men (PADAM): TU appears to be a potentially effective, safe, easy-to-use treatment, worth considering for this purpose. There is no evidence that oral TU has negative effects on the liver or the prostate. Ongoing safety monitoring is essential particularly if TU is used in older men in whom the risks, for example with respect to the prostate, are greatest. References: 1. Gray A, Feldman HA, McKinlay JB et al. Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Ageing Study. J Clin Endocrinol Metab 1991; 73: Vermeulen A. Androgens in the ageing male. J Clin Endocrinol Metab 1991; 73: Tenover JS. Effects of testosterone supplementation in th ageing male. J Clin Endocrinol Metab 1992; 75: Gooren LJF. The age-related decline of androgen levels in men: clinically significant? Br J Urol 1996; 78: Morley JE, Kaiser Fe, Perry III HM, Patrick P, Morley PMK, Stauber PM. Longitudinal changes in testosterone, luteinizing hormone, and folliclestimulating hormone in healthy older men. Metabolism 1997; 46: Bremner WJ, Vitello MV, Prinz PN. Loss of circadian rhythmicity in blood testosterone levels with ageing in normal men. J Clin Endocrinol Metab 1983; 56: Tremblay RR, Morales A. Canadian practice recommendations for screening, monitoring, and treating men affected by andropause or partial androgen deficiency. Ageing Male 1998; 1: Tenover JS. Testosterone and the ageing male. J Androl 1997; 18: Bhasin S, Bremner WJ. Emerging issues in androgen replacement therapy. J Clin Endocrinol Metab 1997; 82: Vermeulen A. The male climacterium. Ann Med 1993; 25: Ferrini RL, Barrett-Connor E. Sex hormones and age: a cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men. Am J Epidemiol 1998; 147: Morley JE, Kaiser F, Raum WJ, Perry III HM, Flood JF, Jensen J. Potentially predictive and manipulable blood stream correlates of ageing in the healthy human male: progressive decreases in bioavailable testosterone, dehydroepiandrosterone sulfate, and the ratio of insulin-like growth factor 1 to growth hormone. Proc Natl Acad Sci USA 1997; 94: Nahoul K, Roger M. Age related decline of plasma bioavailable testosterone in adult men. J Steroid Biochem Mol Biol 1990; 35: Morley JE, Kaiser FE, Sih R, Hajjar R, Perry II HM. Testosterone and frailty. Clin Geriatr Med 1997; 13: Poor G, Atkinson EJ, Lewallen DG, O Fallon WM, Melton LJ. Age-related hip fractures in men: clinical spectrum and short-term outcomes. Osteoporos Int 1995; 5: Seeman E. Hip fractures and osteoporosis in men. MJA 1997; 167: Stanley HL, Schmitt BP, Poses RM, Deiss WP. Does hypogonadism contribute to the occurrence of minimal trauma hip fracture in elderly men? J Am Ger Soc 1991; 39: Daniell HW. Osteoporosis after orchiectomy for prostate cancer. J Urol 1997; 157: Behre HM, Kliesch S, Leifke E, Link TM, Nieschlag E. Long-term effect of testosterone therapy on bone mineral density in hypogonadal men. J Clin Endocrinol Metab 1997; 82: Wong FH, Pun KK, Wang C. Loss of bone mass in patients with Klinefelter s syndrome despite sufficient testosterone replacement. Osteoporos Int 1993; 3: Morley JE, Perry HM 3d, Kaiser FE, Kraenzle D, Jensen J, Houston K et al. Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc 1993; 41: Schow DA, Redmon M, Pryor JL. Male menopause. Postgrad Med 1997; 101: Mooradian AD, Morley JE, Korenman SG. Biological actions of androgens. Endocr Rev 1987; 8: Urban RJ, Bodenburg YH, Gilkison C, Foxworth J, Coggan AR, Wolfe RR et al. Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am J Physiol 1995; 269: E Sih R, Morley JE, Kaiser FE, Perry III HM, Ping P, Ross C. Testosterone replacement in older hypogonadal men: a 12- month randomised controlled trial. J Clin Endocrinol Metab 1997; 82: J. UROL. UROGYNÄKOL. 1/2000 Special Edition 33

12 Prof. Herjan J. T. Coelingh Bennink Prof. Herjan Coelingh Bennink is gynaecologist and Professor of Reproductive Medicine at the Free University in Brussels. Until September 2000 he worked for about 14 years at NV Organon, lastly as Director of the Research and Development Programme for Reproductive Medicine. This included the responsibility for the RM pipeline and strategy, the genomics oriented research in biotechnology, biochemistry, pharmacology, pharmacy, toxicology, drug metabolism, chemical development and registration. From October 2000 Prof. Coelingh Bennink is Director of the Institute of Concept Research in Reproductive Endocrinology (INCORE bioscience) in the Netherlands and CEO of OSTEOPRO in Copenhagen, Denmark, focussing on research on osteoporosis and metastatic bone diseases. Correspondence to: Prof. Dr. H. J. T. Coelingh Bennink NL-3971 BE Driebergen, Melvill van Carnbeelaan Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychsocial correlates: results of the Massachusetts Male Ageing Study. Jurol 1994; 151: Davidson JM, Chen JJ, Crapo L, Gray G, Greenleaf WJ, Catania JA. Hormonal changes and sexual function in ageing men. J Clin Endocrinol Metab 1983; 57: Schiavi RC, Schreiner-Engel P, White D, Mandali J. The relationship between pituitary gonadal function and sexual behavior in healthy ageing men. Psychosom Med 1991; 53: Gooren LJG. Androgen levels and sex functions in testosterone-treated hypogonadal men. Arch Sex Behav 1987; 16: Luisi M, Franchi F. Double-blind group comparative study of testosterone undecanoate and mesterolone in hypogonadal male patients. J Endocrinol Invest 1980; 3: Skakkebaek NE, Bancroft J, Davidson DW, Warner P. Androgen replacement with oral testosterone undecanoate in hypogonadal men: a double blind controlled study. Clin Endocrinol 1981; 14: Carani C, Zini D, Baldini A, Della Casa L, Ghizzani A, Marrama P. Effects of androgen treatment in impotent men with normal and low levels of free testosterone. Arch Sex Behav 1990; 19: Isidori A, Conte D, dal Lago A, di Luigi L, Nordico M, Romanelli F. Effetti del testosterone undecanoato sull attività biologica della gonadotropin LH nella sindrome climaterica maschile. Fisiopatol Riproduzione 1988; 6: Romanelli R, Cini F, Barletta D, Rormoll P, Franchi F, Alicicco E et al. Un nuovo tipi di terapia androgenica nel climaterio maschile. (A new type of androgen therapy for male climacteric.) In: Giornate Endocrinologiche Pisane; sotto gli auspici della Societa Italiana die Endocrinologia Vol 11; 1977 Nov 11 12; Pacini, Pisa, Italy, 1978; Shahidi NT. Androgens and erythropoiesis. N Engl J Med 1973; 289: Jockenhövel F, Vogel E, Reinhardt W, Reinwein D. Effects of various modes of androgen substitution therapy on erythropoiesis. Eur J Med Res 1997; 2: Flood JF, Farr SA, Kaiser FE, La Regina M, Morley JE. Age-related decrease of plasma testosterone in SAMP8 mice: replacement improves age-related impairment of learning and memory. Physiol Behav 1995: 57: Koss E, Haxby HW, DeCarli C, Shapiro MB, Friedland RP, Rapoport SI. Patterns of performance preservation and loss in healthy ageing. Dev Neurospychol 1991; 7: Janowsky JS, Oviatt SK, Orwoll ES. Testosterone influences spatial cognition in older men. Behav Neurosci 1994; 108: Franchi F, Luisi M, Kicovic PM. Long-term study of oral testosterone undecanoate in hypogonadal males. Int J Androl 1978; 1: Franchimont P, Kikovic PM, Mattei A, Roulier R. Effects of oral testosterone undecanoate in hypogonadal male patients. Clin Endocrinol 1978; 9: Maisey NM, Bingham J, Marks V, English J, Chakraborty J. Clinical efficacy of testosterone undecanoate in male hypogonadism. Clin Endocrinol 1981; 14: Papadimas J, Bili E, Papadopoulou F, Spanos E, Tarlatzis B, Kokkas B. Testosterone undecanoate versus mesterolone in hypoganadal male patients. Rev Clin Pharmacol Pharmokinet Int 1996; 10: Marin P, Holmäng S, Jönsson L, Sjöström L, Kvist H, Golm G. The effects of testosterone treatment on body composition and metabolism in middleaged obese men. effects on metabolism, muscle and adipose tissues. Eur J Med. 1992; 1: O Carroll RE, Bancroft J. Androgens and aggression in man: a controlled case study. Aggress Behav 1985; 11: J. UROL. UROGYNÄKOL. 1/2000 Special Edition

13 46. Tenover JS. Androgen administration to ageing male. J Androl 1994; 23: Bhasin S, Tenover JS. Age-associated sarcopenia-issues in the use of testosterone as an anabolic agent in older men. J Clin Endocrinol Metab 1997; 82: Bancroft J, Wu FCW. Changes in erectile responsiveness during androgen replacement therapy. Arch Sex Behav 1983; 12: Conway AJ, Boylan LM, Howe C, Ross G, Handelsman DJ. Randomized clinical trial of testosterone replacement therapy in hypogonadal men. Int J Androl 1988: 11: Franchi F et al. Dosaggio degli steroidi salivari nel monitoraggio della terapia con androgeni negli ipogonadismi maschili. IN Attualità in Andrologia; 4. Congresso Nazionale della Società Italiana die Andrologiea; 1984 Dec 5-8, Bari. Monduzzi Editore, Bologna, 1985; Morales A, Johnston B, Heaton JPW, Lunide M. Testosterone supplementation for hypogonadal impotence: assessment of biochemical measures and therapeutic outcomes. J Urol 1997; 157: Wu FCW, Bancroft J, Davidson DW, Nicol K. The behavioural effects of testosterone undecanoate in adult men with Klinefelter s syndrome: a controlled study. Clin Endocrinol 1982; 16: J. UROL. UROGYNÄKOL. 1/2000 Special Edition 35

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